A group of proteins called molecular chaperones have various functions such as the formation promotion or maintenance of functional structures of other proteins, the promotion of normal association, the prevention of unnecessary aggregation, protection from degradation, and the promotion of secretion (Non Patent Document 1). The molecular chaperone HSP90 is found as abundant as approximately 1 to 2% of all intracellular soluble proteins and, unlike other chaperone proteins, is not required for the biosynthesis of the majority of polypeptides (Non Patent Document 1). Signaling-related factors (e.g., ERBB1/EGFR, ERBB2/HER2, MET, IGF1R, KDR/VEGFR, FLT3, ZAP70, KIT, CHUK/IKK, BRAF, RAF1, SRC, and AKT), cell cycle regulatory factors (e.g., CDK4, CDK6, Cyclin D, PLK1, and BIRC5), and transcriptional regulators (e.g., HIF-1α, p53, androgen receptor, estrogen receptor, and progesterone receptor) are known as main client proteins whose structural formation or stability is controlled through interaction with HSP90 (Non Patent Documents 2 and 3). HSP90 is deeply involved in cell growth and survival by maintaining the normal functions of these proteins. In addition, HSP90 is required for the normal functions of mutant or chimeric factors (e.g., BCR-ABL and NPM-ALK) which cause malignant transformation or cancer exacerbation, indicating the importance of HSP90, particularly, for processes such as malignant transformation and the survival, growth, exacerbation, and metastasis of cancer (Non Patent Document 2).
When the chaperone functions of HSP90 are suppressed by a specific inhibitor such as geldanamycin, its client protein is inactivated, destabilized, and degraded, resulting in induced cell growth arrest or apoptosis (Non Patent Document 4). In terms of the physiological functions of HSP90, such an HSP90 inhibitor is characterized by being capable of simultaneously inhibiting a plurality of signaling pathways involved in cancer survival and growth and as such, can serve as a drug having extensive and effective anticancer effects. Also, the HSP90 inhibitor is expected to serve as a drug with high cancer selectivity from the finding that cancer cell-derived HSP90 is more highly active than normal cell-derived HSP90 and has high affinity for ATP or inhibitors (Non Patent Document 5).
A plurality of HSP90 inhibitors are currently under clinical development as anticancer agents. Development of the geldanamycin derivative 17-allylamino-17-desmethoxygeldanamycin (17-AAG), which is most ahead of others, is underway as a single agent and is also under trial in combination with various anticancer agents (Non Patent Documents 3 and 4). Unfortunately, the problems of 17-AAG, such as poor solubility, instability in solutions, low oral absorbability, and hepatotoxicity, have been pointed out (Non Patent Documents 4 and 5). Thus, a new type of HSP90 inhibitor has been demanded. Reportedly, these HSP90 inhibitors not only have anticancer effects but may serve as therapeutic agents for, for example, autoimmune diseases, inflammatory diseases, central nervous system diseases (such as Parkinson's disease, Alzheimer's disease, and Huntington's disease), viral infectious diseases, cardiovascular diseases (Non Patent Documents 2 and 6).